WO1995017397A1 - Antagonistes des recepteurs du fibrinogene - Google Patents

Antagonistes des recepteurs du fibrinogene Download PDF

Info

Publication number
WO1995017397A1
WO1995017397A1 PCT/US1994/014706 US9414706W WO9517397A1 WO 1995017397 A1 WO1995017397 A1 WO 1995017397A1 US 9414706 W US9414706 W US 9414706W WO 9517397 A1 WO9517397 A1 WO 9517397A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
arylc
alkyloxy
carboxyc
oxo
Prior art date
Application number
PCT/US1994/014706
Other languages
English (en)
Inventor
George D. Hartman
Melissa Egbertson
Laura M. Vassallo
Laura A. Libby
Original Assignee
Merck & Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU14416/95A priority Critical patent/AU1441695A/en
Publication of WO1995017397A1 publication Critical patent/WO1995017397A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • This invention relates to the discovery of fibrinogen receptor antagonists of Formula I for use in inhibiting the binding of fibrinogen to blood platelets and inhibiting the aggregation of blood platelets when administered to mammals, preferably humans.
  • the interaction of platelets with the coagulation and fibrinolytic systems in the maintenance of hemostasis may become pathogenic, requiring prevention and treatment.
  • the fibrinogen receptor antagonists of Formula I are useful in treating various diseases related to platelet aggregation and fibrin formation.
  • Platelets are cell-like anucleated fragments, found in the blood of all mammals which participate in blood coagulation.
  • Fibrinogen is a glycoprotein present as a normal component of blood plasma.
  • Fibrinogen participates in platelet aggregation and fibrin formation in the blood clotting mechanism. Platelets are deposited at sites of vascular injury where multiple physiological agonists act to initiate platelet aggregation culminating in the formation of a platelet plug to minimize blood loss. If the platelet plug occurs in the lumen of a blood vessel, normal blood flow is impaired. Platelet membrane receptors are essential in the process of platelet adhesion and aggregation. Interaction of fibrinogen with a receptor on the platelet membrane complex ITb/IIIa is known to be essential for normal platelet function.
  • Zimmerman et al. U.S. Patent No. 4,683,291
  • the peptides are described as having utility where it is desirable to retard or prevent formation of a thrombus or clot in the blood.
  • Ruoslahti et al U.S. Patent No. 4,614,517, describes tetrapeptides which alter cell-attachment activity of cells to various substrates.
  • Alig et al., EP 372,486, describe N-aryl beta-amino acids which inhibit fibrinogen, fibronectin and von Willebrand factor to the blood platelet fibrinogen receptor (glyco-protein Ilb/IIIa).
  • Alig et al., EP 381 ,033, describe di-aryl or heteroaryl substituted alkanoic acid derivatives of a defined formula which inhibit binding of proteins to their specific receptors on cell surfaces, including fibrinogen.
  • Alig et al., EP 384,362 describe glycine peptides of a specified formula containing an amidine group which inhibit binding of fibrinogen to platelet fibrinogen receptors.
  • phenethylamine derivatives which are useful for treating obesity, hypersecretion of gastric acid in the gut, gastrin-dependent tumors, or as antipsychotics.
  • the present invention provides fibrinogen receptor antagonist compounds of the formula:
  • the above-mentioned compounds can be used in a method of acting upon a fibrinogen receptor which comprises administering a therapeutically effective but non-toxic amount of such compound to a mammal, preferably a human.
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and, dispersed therein, an effective but non-toxic amount of such compound is another feature of this invention.
  • Fibrinogen receptor antagonist compounds of Formula I are useful in a method of inhibiting the binding of fibrinogen to blood platelets and for inhibiting the aggregation of blood platelets. Fibrinogen receptor antagonists of this invention are illustrated by compounds having the formula:
  • A, B, C and D independently represent a carbon atom or a nitrogen atom
  • n 1-4;
  • R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of hydrogen,
  • Y is C 0-8 alkyl
  • R 6 groups may be substituted or unsubstituted independently with R 1 or R 2 , and provided that, when two R 6 groups are attached to the same carbon, they may be the same or different;
  • arylC 0-6 alkylthiocarbonylamino C 0-6 alkyl wherein groups may be unsubstituted or substituted with one or more substituents selected from R 1 and R 2 , and provided that when two R 7 groups are attached to the same carbon atom, they may be the same or different; R 8 is
  • substituent R 1 , R 2 , R 3 , R 4 , R 5 , R 6, R 7 , R 8 or Y includes the definition C 0 , (e.g. aryl C 0 alkyk), the group modified by C 0 is not present in the substituent.
  • Aryl means a mono- or polycyclic system composed of 5-and 6- membered aromatic rings containing 0, 1 , 2, 3 or 4 heteroatoms chosen from N, O or S and either unsubstituted or substituted with R 1 .
  • Alkyl means straight or branched chain alkane, alkene or alkyne.
  • Halogen includes fluorine, chlorine, iodine and bromine.
  • E is -(CH 2 ) n -;
  • n 1-4; X, Y, R 1 , R 2 , R 3 , R 4 , R 6 , R 7 and R 8 are as previously defined.
  • E is -(CH 2 ) n -;
  • n 1-4;
  • R 1 and R 2 are independently chosen from:
  • Preferred compounds of the invention are:
  • compounds of the present invention can be made according to a procedure including the following steps: a) preparing a triflate activated aromatic group of the following general formula:
  • X is an N-terminus protected primary amine, or a primary amine protected directly following this cyclization step; e) converting the C-terminus ester, via hydrolysis, to an acid
  • the procedure involves a) preparing an activated aryl group:
  • X is an N-terminus protected primary amine, or a primary amine protected directly following this cyclization step; e) converting the C-terminus ester, via hydrolysis, to an acid
  • An ADP-stimulated platelet aggregation assay was used to determine inhibition associated with compounds of the invention.
  • Human platelets were isolated from fresh blood, collected into acid citrate/dextrose by differential centrifugation followed by gel filtration on Sepharose 2B in divalent ion-free Tyrode's buffer (pH 7.4) containing 2% bovine serum albumin. Platelet aggregation was measured at 37°C in a a Chronolog aggregometer.
  • the reaction mixture contained gel-filtered human platelets (2 ⁇ 108 per ml), fibrinogen (100 ⁇ g/ml), Ca 2+ (1 mM), and the compound to be tested. Aggregation was initiated by adding 10 uM ADP 1 minute after the other components had been added. The reaction was allowed to proceed for at least 2 minutes.
  • IC 50 is the dose of a particular compound inhibiting aggregation by 50% relative to a control lacking the compound. Additional preferred embodiments of the invention, shown below with platelet aggregation inhibition potency data (IC 50 ⁇ M) are:
  • TBDMS tert-butyldimethylsilyl
  • Jones reagent chromic acid
  • NBS N-Bromosuccinimide
  • BPO Benzoyl peroxide
  • PPh3 triphenyl phosphine
  • DMSO Dimethylsulfoxide
  • Et 3 N triethylamine
  • Tf 2 O triflic anhydride
  • DMAP 4-dimethylaminopyridine
  • BOP benzotriazol-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate
  • PhCHO benzaldehyde
  • Boc 2 O di-t-butyldicarbonate
  • dppp 1 ,3-bis(diphenylphosphino)propane
  • ETOH ethyl acetate
  • CH 2 CI 2 methylene chloride
  • HOAc acetic acid
  • CH 3 OH methanol
  • CHCI 3 chloroform.
  • the pharmaceutically acceptable salts of the compounds of Formula I include the conventional non-toxic salts or the quarternary ammonium salts of the compounds of Formula I formed, e.g., from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as
  • organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzo
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of Formula I which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents.
  • Formula I are also readily prepared by conventional procedures such as treating an acid of Formula I with an appropriate amount of a base, such as an alkali or alkaline earth metal hydroxide e.g. sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g., dibenzylethylenediamine, trimethylamine, piperidine, pyrrolidine, benzylamine and the like, or a quaternary ammonium hydroxide such as tetramethylammonium hydroxide and the like.
  • a base such as an alkali or alkaline earth metal hydroxide e.g. sodium, potassium, lithium, calcium, or magnesium
  • an organic base such as an amine, e.g., dibenzylethylenediamine, trimethylamine, piperidine, pyrrolidine, benzylamine and the like, or a quaternary ammonium hydroxide such as tetramethylammonium hydroxide and the like.
  • the compounds of Formula I are useful in inhibiting the binding of fibrinogen to blood platelets, inhibiting aggregation of blood platelets, treatment of thrombus formation or embolus formation, and in the prevention of thrombus formation or embolus formation. These compounds are useful as pharmaceutical agents for mammals, especially for humans.
  • the compounds of this invention may be administered to patients where prevention of thrombosis by inhibiting binding of fibrinogen to the platelet membrane glycoprotein complex IIb/ ⁇ ia receptor is desired.
  • Compounds of this invention may also be used to prevent or modulate the progress of myocardial infarction, unstable angina and thrombotic stroke, in either acute or chronic settings.
  • peripheral arteries arterial grafts, carotid endarterectomy
  • cardiovascular surgery where manipulation of arteries and organs, and/or the interaction of platelets with artificial surfaces, leads to platelet aggregation and consumption.
  • the aggregated platelets may form thrombi and thromboemboli.
  • Compounds of this invention may be administered to surgical patients to prevent the formation of thrombi and thromboemboli.
  • Extracorporeal circulation is routinely used for cardiovascular surgery in order to oxygenate blood. Platelets adhere to surfaces of the extracorporeal circuit. Adhesion is dependent on the interaction between GPIIb/IIIa on the platelet membranes and fibrinogen adsorbed to the surface of the circuit. (Gluszko et al., Amer. J. Physiol., 1987, 252:H, pp 615-621). Platelets released from artificial surfaces show impaired hemostatic function. Compounds of this invention may be administered to prevent adhesion.
  • the compounds of Formula I may be administered to mammals, preferably in combination with pharmaceutically-acceptable carriers or diluents, optionally with known adjuvants such as alum, in a pharmaceutical composition which is non-toxic and in a therapeutically effective amount, according to standard pharmaceutical practice.
  • the compounds can be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, trans-dermal, subcutaneous and topical administration.
  • the selected compounds may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension.
  • carriers which are commonly used include lactose and corn starch, and lubricating agents, such as magnesium stearate, are commonly added.
  • useful diluents include lactose and dried corn starch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added.
  • sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered.
  • the total concentration of solutes should be controlled in order to render the preparation isotonic.
  • the present invention also encompasses a pharmaceutical composition useful in the treatment and prevention of diseases related to platelet aggregation, fibrin formation, and thrombus and embolus formation, comprising the administration of a therapeutically effective but non-toxic amount of the compounds of Formula I, with or without pharmaceutically acceptable carriers or diluents.
  • compositions of this invention include fibrinogen receptor antagonist compounds of this invention in combination with pharmacologically acceptable carriers, e.g. saline, at a pH level e.g. 7.4, suitable for achieving inhibition of platelet aggregation.
  • pharmacologically acceptable carriers e.g. saline
  • the compositions may also be combined with anticoagulants such as heparin or warfarin.
  • anticoagulants such as heparin or warfarin.
  • throm-bolytic agents such as plasminogen activators or streptokinase in order to inhibit platelet aggregation in more acute settings.
  • the composition may further be combined with antiplatelet agents such as aspirin.
  • the compositions are soluble in an aqueous medium, and may therefore be effectively administered in solution.
  • the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patients symptoms.
  • a suitable amount of compound is administered orally to a heart attack victim subsequent to angioplasty.
  • Administration occurs subsequent to angioplasty, and is in an amount sufficient to inhibit platelet aggregation, e.g. an amount which achieves a steady state plasma concentration of between about 0.01-50 ⁇ M preferably between about 0.01 -10 ⁇ M.
  • the present invention also includes a pharmaceutical composition comprising compounds of the present invention in
  • the invention also includes a method for promoting thrombolysis and preventing reocclusion in a patient which comprises administering to the patient an effective amount of compositions of the invention.
  • the present invention provides a method of inhibiting the binding of fibrinogen to blood platelets, inhibiting aggregation of blood platelets, treating thrombus formation or embolus formation, and in preventing thrombus formation or embolus formation in a mammal, comprising the administration of a therapeutically effective but non-toxic amount of the compounds of this invention, with or without
  • the present invention still further provides a method of inhibiting the binding of fibrinogen to blood platelets, inhibiting aggregation of blood platelets, treating thrombus formation or embolus formation, and in preventing thrombus formation or embolus formation in a mammal, comprising the administration of a therapeutically effective but non-toxic amounts of the compounds of this invention in combination with thrombolytic agents, such as tissue plasminogen activators or streptokinase, anticoagulants such as heparin or warfarin, or antiplatelet agents such as aspirin, with or without pharmaceutically acceptable carriers or diluents.
  • thrombolytic agents such as tissue plasminogen activators or streptokinase, anticoagulants such as heparin or warfarin, or antiplatelet agents such as aspirin, with or without pharmaceutically acceptable carriers or diluents.
  • Boc-4-piperidine-2-ethanol (1-5) (10.42 g, 0.048 mole was dissolved in 400 ml benzene and imidazole (4.66 g, 0.068 moles) and triphenylphosphine (15.24 g, 0.05 moles) were added at room
  • the resulting reaction mixture was extracted with ether (3 ⁇ 200 ml) and then made basic with 1N KOH solution and extracted with CHCI 3 (4 ⁇ 75 ml). The combined organic extract was washed with brine, dried (Na 2 SO 4 ) filtered through celite, and the solvent removed to provide pure 2 -3 as a clear oil.
  • THF(1)/MeOH(1)/H 2 O(1) was treated with LiOH•H 2 O (1.20 g, 28.6 mmoles) at room temperature and the resulting solution was stirred for 1.0 hr. The solvent was then removed and the residue was taken up in H 2 O (100 ml) acidified to pH 2 with 10% KHSO 4 solution. The desired acid precipitated from solution and was collected.
  • This acid (1.62 g, 4.91 mmoles) was dissolved in CH 3 CN (25 ml) and treated at 0° successively with Et 3 N (34.4 mmoles), ⁇ -alanine ethyl ester (5.0 mmoles), and BOP (3.27 g, 7.38 mmoles). The reaction mixture was then stirred at room temperature for 16 hrs. The solvent was removed and the residue purified by flash chromatography in silica gel eluting with EtOAc (7)/)exane (1) to provide 2-5 as a white solid.
  • THF(1)/MeOH(1)/H 2 O(1) was treated with LiOH•H 2 O (0.45 g, 10.7 mmoles) at room temperature and the resulting solution was stirred at room temperature for 1.0 hr.
  • the solvent was removed and the residue was dissolved in H 2 O (25 ml), acidified to pH 2-3 with 10% KHSO 4 solution and extracted with EtOAc (4 ⁇ 25 ml).
  • the combined organic extracts were washed with brine, dried (Na 2 SO 4 ) and the solvent removed to give the desired acid as a white solid.
  • This acid (0.80 g, 1.89 mmoles) was treated with HCI gas in EtOAc solution as described for 2-3 to provide pure 2-6 as a white solid.
  • 2-5 can also be converted to 2-7 as shown below:
  • This iodo compound (3.9 g, 16 mmoles) was dissolved in DMSO (80 ml) and treated with NaN 3 (2.1 g, 32 mmoles) at 70° for 2 hours. The cooled reaction next was diluted with EtOAc and extracted with H 2 O and brine. The organic phase was washed with brine, dried (Na 2 SO 4 ) and the solvent was removed to give the desired azide as a foam.
  • Methyl 2(S)-amino-3-(N-t-butyloxycarbonyl)aminopropionate 23-4 (16.8 g, 0.077 mole) dissolved in 330 mL methylene chloride was treated with sulfonyl chloride 23-10 (20.6 g, 0.1 16 mole) and pyridine (12.5 mL, 0.154 mole) and the reaction was stirred for 21 hours. The reaction was concentrated, absorbed to silica and
  • Methyl 2(S)-(3-pyridylsulfonyl)amino-3-(N-t-butyloxycarbonyl)aminopropionate 23-1 1 (17.5 g, 0.049 mole) was suspended in 200 mL EtOAc and cooled to -78°C. HCI gas was bubbled through the solution for ten minutes and the solution was then placed in an ice bath. After stirring for 40 minutes at 0°C, no starting material could be detected by TLC. The solution was concentrated, first at room temperature, then at 40°C to yield 23-12 as an off-white solid.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Antagonistes des récepteurs du fibrinogène selon la formule (I), destinés à inhiber la liaison du fibrinogène sur les plaquettes sanguines et à inhiber l'agrégation plaquettaire, dans lesquels G est (a) ou (b).
PCT/US1994/014706 1993-12-20 1994-12-19 Antagonistes des recepteurs du fibrinogene WO1995017397A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU14416/95A AU1441695A (en) 1993-12-20 1994-12-19 Fibrinogen receptor antagonists

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US169,904 1993-12-20
US08/169,904 US5416099A (en) 1991-10-29 1993-12-20 Fibrinogen receptor antagonists

Publications (1)

Publication Number Publication Date
WO1995017397A1 true WO1995017397A1 (fr) 1995-06-29

Family

ID=22617692

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1994/014706 WO1995017397A1 (fr) 1993-12-20 1994-12-19 Antagonistes des recepteurs du fibrinogene

Country Status (3)

Country Link
US (1) US5416099A (fr)
AU (1) AU1441695A (fr)
WO (1) WO1995017397A1 (fr)

Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5760028A (en) * 1995-12-22 1998-06-02 The Dupont Merck Pharmaceutical Company Integrin receptor antagonists
EP0866705A1 (fr) * 1995-10-19 1998-09-30 Merck & Co., Inc. Antagonistes du recepteur de fibrinogene
WO1999031099A1 (fr) * 1997-12-17 1999-06-24 Merck & Co., Inc. Antagonistes du recepteur de l'integrine
EP0934305A1 (fr) * 1996-08-29 1999-08-11 Merck & Co., Inc. Antagonistes de l'integrine
EP1047425A1 (fr) * 1997-12-17 2000-11-02 Merck & Co., Inc. Antagonistes du recepteur de l'integrine
WO2002096873A1 (fr) * 2001-05-31 2002-12-05 Millennium Pharmaceuticals, Inc. Inhibiteurs du facteur xa a base de derives isoindole et isoquinoline
US8691849B2 (en) 2008-09-02 2014-04-08 Janssen Pharmaceuticals, Inc. 3-azabicyclo[3.1.0]hexyl derivatives as modulators of metabotropic glutamate receptors
US8691813B2 (en) 2008-11-28 2014-04-08 Janssen Pharmaceuticals, Inc. Indole and benzoxazine derivatives as modulators of metabotropic glutamate receptors
US8841323B2 (en) 2006-03-15 2014-09-23 Janssen Pharmaceuticals, Inc. 1, 4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of MGLUR2-receptors
US8906939B2 (en) 2007-03-07 2014-12-09 Janssen Pharmaceuticals, Inc. 3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives
US8937060B2 (en) 2009-05-12 2015-01-20 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders
US8946205B2 (en) 2009-05-12 2015-02-03 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US8993591B2 (en) 2010-11-08 2015-03-31 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a] pyridine derivatives and their use as positive allosteric modulators of MGLUR2 receptors
US9012448B2 (en) 2010-11-08 2015-04-21 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of MGLUR2 receptors
US9067891B2 (en) 2007-03-07 2015-06-30 Janssen Pharmaceuticals, Inc. 1,4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of mGluR2-receptors
US9085577B2 (en) 2009-05-12 2015-07-21 Janssen Pharmaceuticals, Inc. 7-aryl-1,2,4-triazolo[4,3-A]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US9114138B2 (en) 2007-09-14 2015-08-25 Janssen Pharmaceuticals, Inc. 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′] bipyridinyl-2′-ones
US9266886B2 (en) 2014-02-03 2016-02-23 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9271967B2 (en) 2010-11-08 2016-03-01 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US9481674B1 (en) 2016-06-10 2016-11-01 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9663515B2 (en) 2014-11-05 2017-05-30 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9708315B2 (en) 2013-09-06 2017-07-18 Janssen Pharmaceutica Nv 1,2,4-triazolo[4,3-a]pyridine compounds and their use as positive allosteric modulators of MGLUR2 receptors
US9796710B2 (en) 2014-10-14 2017-10-24 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9845308B2 (en) 2014-11-05 2017-12-19 Vitae Pharmaceuticals, Inc. Isoindoline inhibitors of ROR-gamma
US10106542B2 (en) 2013-06-04 2018-10-23 Janssen Pharmaceutica Nv Substituted 6,7-dihydropyrazolo[1,5-a]pyrazines as negative allosteric modulators of mGluR2 receptors
US10301261B2 (en) 2015-08-05 2019-05-28 Vitae Pharmaceuticals, Llc Substituted indoles as modulators of ROR-gamma
US10537573B2 (en) 2014-01-21 2020-01-21 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
US10829481B2 (en) 2016-01-29 2020-11-10 Vitae Pharmaceuticals, Llc Benzimidazole derivatives as modulators of ROR-gamma
US10913739B2 (en) 2017-07-24 2021-02-09 Vitae Pharmaceuticals, LLC (121374) Inhibitors of RORγ
US11008340B2 (en) 2015-11-20 2021-05-18 Vitae Pharmaceuticals, Llc Modulators of ROR-gamma
US11186573B2 (en) 2017-07-24 2021-11-30 Vitae Pharmaceuticals, Llc Inhibitors of ROR gamma
US11369606B2 (en) 2014-01-21 2022-06-28 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6087380A (en) * 1949-11-24 2000-07-11 Boehringer Ingelheim Pharma Kg Disubstituted bicyclic heterocycles, the preparations and the use thereof as pharmaceutical compositions
DE69327536T2 (de) * 1992-10-14 2000-07-06 Merck & Co., Inc. Fibrinogenrezeptor-antagonisten
US5925655A (en) * 1996-04-10 1999-07-20 Merck & Co., Inc. αv β3 antagonists
US5919792A (en) * 1996-10-30 1999-07-06 Merck & Co., Inc. Integrin antagonists
AU717283B2 (en) * 1996-10-30 2000-03-23 Merck & Co., Inc. Integrin antagonists
PE121699A1 (es) * 1997-02-18 1999-12-08 Boehringer Ingelheim Pharma Heterociclos biciclicos disustituidos como inhibidores de la trombina
US20030181488A1 (en) * 2002-03-07 2003-09-25 Boehringer Ingelheim Pharma Gmbh & Co. Kg Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester and the salts thereof
DE10339862A1 (de) * 2003-08-29 2005-03-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg 3-[(2-{[4-(Hexyloxycarbonylamino-imino-methyl)- phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionsäure-ethylester-Methansulfonat und dessen Verwendung als Arzneimittel
DE102005025728A1 (de) * 2005-06-04 2006-12-07 Boehringer Ingelheim Pharma Gmbh & Co. Kg Polymorphe von 3-[(2-{[4-(Hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-Propionsäure-ethylester
US11043823B2 (en) * 2017-04-06 2021-06-22 Tesla, Inc. System and method for facilitating conditioning and testing of rechargeable battery cells

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0540334A1 (fr) * 1991-10-29 1993-05-05 Merck & Co. Inc. Antagonistes du récepteur fibrinogène

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3322631A (en) * 1965-06-30 1967-05-30 Merck & Co Inc Method of treatment of hypertension
US4010274A (en) * 1973-07-27 1977-03-01 Carlo Erba Isoindoline derivatives having platelet anti-aggregating activity
US4313947A (en) * 1974-06-24 1982-02-02 Otsuka Pharmaceutical Co., Ltd. Platelet aggregation inhibiting 2-oxyindoles, their compositions and method of use
DE2549999A1 (de) * 1975-11-07 1977-05-12 Boehringer Mannheim Gmbh Piperidin-derivate und verfahren zu ihrer herstellung
US4064125A (en) * 1976-10-29 1977-12-20 E. R. Squibb And Sons, Inc. Substituted amides having antiinflammatory activity
EP0021592B1 (fr) * 1979-05-23 1983-09-28 BEECHAM - WUELFING GmbH & Co. KG Dérivés de benzènesulfonamides, procédé pour leur préparation et leur application comme médicaments
KR880007441A (ko) * 1986-12-11 1988-08-27 알렌 제이.스피겔 스피로-치환된 글루타르아미드 이뇨제
US5260316A (en) * 1991-07-30 1993-11-09 Ciba-Geigy Corporation Isoquinolyl substituted hydroxylamine derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0540334A1 (fr) * 1991-10-29 1993-05-05 Merck & Co. Inc. Antagonistes du récepteur fibrinogène

Cited By (52)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0866705A1 (fr) * 1995-10-19 1998-09-30 Merck & Co., Inc. Antagonistes du recepteur de fibrinogene
EP0866705A4 (fr) * 1995-10-19 1999-03-03 Merck & Co Inc Antagonistes du recepteur de fibrinogene
US5760028A (en) * 1995-12-22 1998-06-02 The Dupont Merck Pharmaceutical Company Integrin receptor antagonists
EP0934305A4 (fr) * 1996-08-29 2001-04-11 Merck & Co Inc Antagonistes de l'integrine
EP0934305A1 (fr) * 1996-08-29 1999-08-11 Merck & Co., Inc. Antagonistes de l'integrine
EP1047425A4 (fr) * 1997-12-17 2009-04-22 Merck & Co Inc Antagonistes du recepteur de l'integrine
EP1047425A1 (fr) * 1997-12-17 2000-11-02 Merck & Co., Inc. Antagonistes du recepteur de l'integrine
WO1999031099A1 (fr) * 1997-12-17 1999-06-24 Merck & Co., Inc. Antagonistes du recepteur de l'integrine
WO2002096873A1 (fr) * 2001-05-31 2002-12-05 Millennium Pharmaceuticals, Inc. Inhibiteurs du facteur xa a base de derives isoindole et isoquinoline
US8841323B2 (en) 2006-03-15 2014-09-23 Janssen Pharmaceuticals, Inc. 1, 4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of MGLUR2-receptors
US9266834B2 (en) 2006-03-15 2016-02-23 Janssen Pharmaceuticals, Inc. 1, 4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of MGLUR2-receptors
US8906939B2 (en) 2007-03-07 2014-12-09 Janssen Pharmaceuticals, Inc. 3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives
US9067891B2 (en) 2007-03-07 2015-06-30 Janssen Pharmaceuticals, Inc. 1,4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of mGluR2-receptors
US9114138B2 (en) 2007-09-14 2015-08-25 Janssen Pharmaceuticals, Inc. 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′] bipyridinyl-2′-ones
US11071729B2 (en) 2007-09-14 2021-07-27 Addex Pharmaceuticals S.A. 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′]bipyridinyl-2′-ones
US9132122B2 (en) 2007-09-14 2015-09-15 Janssen Pharmaceuticals, Inc. 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′]bipyridinyl-2′-ones
US8691849B2 (en) 2008-09-02 2014-04-08 Janssen Pharmaceuticals, Inc. 3-azabicyclo[3.1.0]hexyl derivatives as modulators of metabotropic glutamate receptors
US8691813B2 (en) 2008-11-28 2014-04-08 Janssen Pharmaceuticals, Inc. Indole and benzoxazine derivatives as modulators of metabotropic glutamate receptors
US8946205B2 (en) 2009-05-12 2015-02-03 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US9085577B2 (en) 2009-05-12 2015-07-21 Janssen Pharmaceuticals, Inc. 7-aryl-1,2,4-triazolo[4,3-A]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US9226930B2 (en) 2009-05-12 2016-01-05 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo [4,3-a] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders
US10071095B2 (en) 2009-05-12 2018-09-11 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of neurological and psychiatric disorders
US8937060B2 (en) 2009-05-12 2015-01-20 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders
US9737533B2 (en) 2009-05-12 2017-08-22 Janssen Pharmaceuticals. Inc. 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders
US9012448B2 (en) 2010-11-08 2015-04-21 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of MGLUR2 receptors
US8993591B2 (en) 2010-11-08 2015-03-31 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a] pyridine derivatives and their use as positive allosteric modulators of MGLUR2 receptors
US9271967B2 (en) 2010-11-08 2016-03-01 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US10584129B2 (en) 2013-06-04 2020-03-10 Janssen Pharmaceuticals Nv Substituted 6,7-dihydropyrazolo[1,5-a]pyrazines as negative allosteric modulators of mGluR2 receptors
US10106542B2 (en) 2013-06-04 2018-10-23 Janssen Pharmaceutica Nv Substituted 6,7-dihydropyrazolo[1,5-a]pyrazines as negative allosteric modulators of mGluR2 receptors
US9708315B2 (en) 2013-09-06 2017-07-18 Janssen Pharmaceutica Nv 1,2,4-triazolo[4,3-a]pyridine compounds and their use as positive allosteric modulators of MGLUR2 receptors
US10537573B2 (en) 2014-01-21 2020-01-21 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
US12048696B2 (en) 2014-01-21 2024-07-30 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
US11103506B2 (en) 2014-01-21 2021-08-31 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
US11369606B2 (en) 2014-01-21 2022-06-28 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
US10807980B2 (en) 2014-02-03 2020-10-20 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US10399976B2 (en) 2014-02-03 2019-09-03 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US9624217B2 (en) 2014-02-03 2017-04-18 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9266886B2 (en) 2014-02-03 2016-02-23 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US11535614B2 (en) 2014-02-03 2022-12-27 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US10047085B2 (en) 2014-02-03 2018-08-14 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US10087184B2 (en) 2014-10-14 2018-10-02 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of RORγ
US9796710B2 (en) 2014-10-14 2017-10-24 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9663515B2 (en) 2014-11-05 2017-05-30 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9845308B2 (en) 2014-11-05 2017-12-19 Vitae Pharmaceuticals, Inc. Isoindoline inhibitors of ROR-gamma
US11001583B2 (en) 2014-11-05 2021-05-11 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US10301261B2 (en) 2015-08-05 2019-05-28 Vitae Pharmaceuticals, Llc Substituted indoles as modulators of ROR-gamma
US10829448B2 (en) 2015-08-05 2020-11-10 Vitae Pharmaceuticals, Llc Substituted benzoimidazoles as modulators of ROR-γ
US11008340B2 (en) 2015-11-20 2021-05-18 Vitae Pharmaceuticals, Llc Modulators of ROR-gamma
US10829481B2 (en) 2016-01-29 2020-11-10 Vitae Pharmaceuticals, Llc Benzimidazole derivatives as modulators of ROR-gamma
US9481674B1 (en) 2016-06-10 2016-11-01 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US10913739B2 (en) 2017-07-24 2021-02-09 Vitae Pharmaceuticals, LLC (121374) Inhibitors of RORγ
US11186573B2 (en) 2017-07-24 2021-11-30 Vitae Pharmaceuticals, Llc Inhibitors of ROR gamma

Also Published As

Publication number Publication date
AU1441695A (en) 1995-07-10
US5416099A (en) 1995-05-16

Similar Documents

Publication Publication Date Title
US5416099A (en) Fibrinogen receptor antagonists
EP0540334B1 (fr) Antagonistes du récepteur fibrinogène
EP0664792B1 (fr) Antagonistes des recepteurs du fibrinogene
US5389631A (en) Fibrinogen receptor antagonists
US5321034A (en) Fibrinogen receptor antagonists
US5281585A (en) Fibrinogen receptor antagonists for inhibiting aggregation of blood platelets
NZ239876A (en) Glycyl-b-alanine derivatives and pharmaceutical compositions thereof.
US5264420A (en) Fibrinogen receptor antagonists
CZ298827B6 (cs) Deriváty indolu jako inhibitory faktoru Xa, zpusob jejich prípravy a farmaceutická kompozice, kteráje obsahuje
JPH11501907A (ja) フィブリノーゲンレセプターアンタゴニスト
US5441952A (en) Fibrinogen receptor antagonists
US5525617A (en) Fibrinogen receptor antagonists
LV10425B (en) Fibrinogen receptor antagonists

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AM AU BB BG BR BY CA CN CZ EE FI GE HU JP KG KR KZ LK LR LT LV MD MG MN NO NZ PL RO RU SI SK TJ TT UA US UZ

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): KE MW SD SZ AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA